Delivering drugs to patients in a safe, effective, and compliant manner is a major challenge for treatment of many types of disease. Effective oral dosing to achieve high concentrations of drugs within specific tissues while minimizing systemic toxicity remains a significant challenge. Additionally, conventional polymeric drug delivery systems such as implants, injectable microspheres, and patches are used by tens of millions of people annually, yet often produce sub-optimal drug release profiles. We aim to develop an autonomous drug delivery system that titrates the amount of drug released in response to a biological stimulus, ensuring the drug is released only when needed at a therapeutically relevant concentration. In collaboration with Dr. Tony Aliprantis, a Rheumatologist at the Brigham and Women's hospital, we aim to demonstrate an in vitro and in vivo proof of concept for this technology in models of inflammatory arthritis. In the U.S. alone, it is estimated that 2.5 million people suffer from rheumatoid arthritis with a monetary cost measured in the billions. This work will assess the hypothesis that drug based hydrogels, containing enzyme labile linkers, that are tailored to disassemble in response to enzymes expressed during exacerbations from inflammatory arthritis can serve as an effective on demand approach for local long term drug delivery to treat inflammatory joint disease. These gels will be tested using a novel in vitro 3-dimensional synovial micromass organ culture method that faithfully replicates many aspects of the synovial lining physiology and architecture. The gels will also be tested in the rodent model of inflammatory arthritis. This application will focus on addressing the following aims: Aim 1: a) Synthesize prodrug-based hydrogels that disassemble in response to MMPs those are upregulated within joints in IA and b) confirm capacity for IA synovial fluid to disassemble prodrug hydrogels in an MMP specific manner. Aim 2: Confirm MMP selectivity and 'on demand' disassembly in synovial micromass organ culture. Aim 3: a) Demonstrate on demand disassembly of MMP specific prodrug hydrogels in vivo and b) Demonstrate capacity for prodrug based hydrogels to ameliorate inflammatory arthritis In vivo.